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ACUTE MYELOID LEUKEMIA

Glasdigib fails to slay the hedgehog in pivotal AML trials

Leukemia volume 37, pages 2520–2521 (2023)Cite this article

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Hedgehogs are small mammals with a coat of sharp spines that protect against most predators. The Hedgehog signaling pathway (Hh), named after this resilient rodent, is widely conserved across many species and is critical for embryonic development. The Hh is also felt to contribute to the survival of stem cells of different organs, with preclinical evidence that overexpression of steps in this pathway can be associated with chemotherapy resistance in acute myeloid leukemia (AML) [1].

Glasdegib is an orally administered inhibitor of Smoothened, a transmembrane component of Hh. Based on the results of a small, randomized phase 2 clinical trial comparing low dose cytarabine (LDAC) with or without glasdegib, the drug was approved by the FDA for the treatment of patients with AML or high risk MDS who were not considered to be candidates for intensive chemotherapy. Complete response rates were low (17% of 88 patients receiving the combination vs. 2% of 44 patients with LDAC alone) with median survivals of 8.8 and 4.9 months respectively in the two groups [2].

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References

  1. Irvine DA, Copland M. Targeting hedgehog in hematologic malignancy. Blood. 2012;119:2196–204.

    Article  CAS  PubMed  Google Scholar 

  2. Cortes JE, Heidel FH, Hellmann A, Fiedler W, Smith BD, Robak T, et al. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia. 2019;33:379–89.

    Article  CAS  PubMed  Google Scholar 

  3. Sekeres MA, Montesinos P, Novak J, Wang J, Jeyakumar D, Tomlinson B, et al. Glasdegib plus intensive or non-intensive chemotherapy for untreated acute myeloid leukemia: results from the randomized, phase 3 BRIGHT AML 1019 trial. Leukemia. 2023;37:2017–26.

  4. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10:223–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Gattermann N, Germing U, et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol. 2010;28:562–9.

    Article  CAS  PubMed  Google Scholar 

  6. Gyawali B, Kesselheim AS, Ross JS. The Accelerated Approval Program for Cancer Drugs - Finding the Right Balance. N Engl J Med. 2023;389:968–71.

    Article  PubMed  Google Scholar 

  7. Hu Y, Charaan M, van Oostrum I, Heeg B, Bell T. The cost-effectiveness of glasdegib in combination with low-dose cytarabine, for the treatment of newly diagnosed acute myeloid leukemia in adult patients who are not eligible to receive intensive induction chemotherapy in Canada. J Med Econ. 2021;24:150–61.

    Article  PubMed  Google Scholar 

  8. DiNardo CD, Wang J, Pratz KW. Azacitidine and Venetoclax in AML. Reply. N Engl J Med. 2020;383:2088–9.

    PubMed  Google Scholar 

  9. Roboz GJ, Kantarjian HM, Yee KWL, Kropf PL, O’Connell CL, Griffiths EA, et al. Dose, schedule, safety, and efficacy of guadecitabine in relapsed or refractory acute myeloid leukemia. Cancer. 2018;124:325–34.

    Article  CAS  PubMed  Google Scholar 

  10. Schiffer CA. “Epigenetic” modification as therapy for acute myeloid leukemia. Cancer. 2018;124:242–4.

    Article  PubMed  Google Scholar 

  11. Wei AH, Montesinos P, Ivanov V, DiNardo CD, Novak J, Laribi K, et al. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood. 2020;135:2137–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

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  1. Emeritus Professor of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R, Detroit, MI, 48201, USA

    Charles A. Schiffer

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  1. Charles A. Schiffer
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Dr CAS conceived of the ideas expressed in the Commentary and wrote the paper.

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Correspondence to Charles A. Schiffer.

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Schiffer, C.A. Glasdigib fails to slay the hedgehog in pivotal AML trials. Leukemia 37, 2520–2521 (2023). https://doi.org/10.1038/s41375-023-02049-x

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